P505: SAFETY AND EFFICACY OF CASEIN KINASE 1Α AND CYCLIN DEPENDENT KINASE 7/9 INHIBITION IN PATIENTS WITH RELAPSED OR REFRACTORY AML: A PHASE 1, FIRST-IN-HUMAN STUDY OF BTX-A51
Authors: B. J. Ball, G. Borthakur, A. Stein, K. W. Chan, D. Thai, E. M. Stein
Journal: HemaSphere (2022)

Background: Inactivation of p53 and overexpression of Mcl1 are common mechanisms that cancer cells use to evade apoptosis. BTX-A51 is a novel, oral, direct inhibitor of casein kinase 1α (CK1α), cyclin dependent kinase 7 (CDK7), and CDK9. CDK7 and CDK9 phosphorylate RNA polymerase II (Pol II) to enable transcriptional initiation and elongation, particularly at large clusters of transcriptional enhancers termed super-enhancers (SE). Preclinical studies have demonstrated that BTX-A51 robustly increased p53 protein levels via CK1α inhibition and Mdm2 downregulation while preferentially decreasing SE transcription of key oncogenes such as Myc and Mcl1, enabling selective apoptosis of leukemia cells. Here, we report the interim results of the phase 1, first-in-human (FIH) study of BTX-A51 in patients (pts) with R/R AML. Aims: 1. To evaluate the safety and preliminary efficacy of BTX-A51 in patients with R/R AML 2. To determine the pharmacokinetics and pharmacodynamics of BTX-A51 Methods: This is an open-label, multi-center, FIH Phase 1 study. The study utilizes a hybrid accelerated titration with single pt cohorts and a Bayesian optimal interval design to assess 9 potential dosing cohorts. Key eligibility criteria include age ≥ 18 years, R/R AML or R/R high-risk MDS, ECOG ≤ 2, adequate kidney and liver function, WBC ≤ 25K/uL. PD studies include digital droplet PCR from PB to quantify target genes and measurement of macrophage inhibitory cytokine level by ELISA from serum at serial timepoints. Results: As of 25 January 2022, 30 pts (28 with AML; 2 with HR-MDS) enrolled at dose levels between 1 and 42mg; 2 pts remain on treatment. Monotherapy doses between 1 and 42 mg were administered orally 3 days/week (wk) (3 wk in a 28-day cycle) and at 21 mg (4 wk in a 28-day cycle). Baseline characteristics include median age 75 years, median number of prior therapies 3, 97% received prior treatment with venetoclax, 97% had prior HMA, and 43% had prior induction failure. The most common treatment-emergent AEs (TEAEs) were nausea (60%), vomiting (52%), hypokalemia (48%), diarrhea (36%), and hypotension (36%). The most common Grade 3 or higher TEAEs were anemia (28%), febrile neutropenia (28%), platelet count decreased (24%), and hypokalemia (20%). The only DLTs were grade 3 hepatic failure at the 42 mg dose and grade 3 alkaline phosphatase elevation at the 21 mg dose. All events resolved after holding study drug. Plasma PK of BTX-A51 was roughly dose-proportional between 1 and 42 mg with accumulation based on AUC between Day 1 and Day 5. Estimated half-life was between 18 and 55 hours. Among the 30 pts with R/R AML and MDS, CR/CRi rate was 10% (3/30) with 1 pt at the 11 mg and 2 pts at the 21 mg dose levels attaining CRi. Bone marrow (BM) blast reduction >50% occurred in 4 patients including the 3 responders, all at the 11 and 21mg dose levels. All 4 pts with >50% BM blast reduction had RUNX1 mutations; 9 pt with RUNX1 enrolled in the trial. The median duration of response for pts achieving CR/CRi was approximately 1.5 month. Responses were not observed in MDS pts. PD data will be provided in the full presentation. Based on the clinical data from dose escalation, the RP2D is 21 mg administered 3 days/wk for 4 wk of a 28-day cycle. Image:Summary/Conclusion: In this FIH study, BTX-A51 demonstrated an acceptable safety profile and promising antileukemic activity in pts with heavily pretreated R/R AML. The 21 mg dose administered 3x/wk for 4 wk was identified as the RP2D. RUNX1 mutations were enriched among responders and pts attaining >50% BM blast reduction.